ORIGINAL ARTICLE The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG) C Buske 1 , E Hoster 1,2 , M Dreyling 1 , H Eimermacher 3 , H Wandt 4 , B Metzner 5 , R Fuchs 6 , J Bittenbring 7 , B Woermann 8 , K Hohloch 9 , G Hess 10 , W-D Ludwig 11 , J Schimke 12 , S Schmitz 13 , M Kneba 14 , M Reiser 15 , U Graeven 16 , W Klapper 17 , M Unterhalt 1 and W Hiddemann 1 1 Department of Internal Medicine III, University of Munich, Campus Grohadern, Munich, Germany; 2 Department of Medical Informatics, Biometry and Epidemiology (IBE), University of Munich, Munich, Germany; 3 Department of Medicine II, Catholic Hospital Hagen, Hagen, Germany; 4 Department of Medicine 5, Hospital Nuernberg North, Nuernberg, Germany; 5 Department of Medicine II, Klinikum Oldenburg, Oldenburg, Germany; 6 Department of Hematology/Oncology, St Antonius Hospital, Eschweiler, Germany; 7 Department of Medicine I, University Medical School Saarland, Homburg, Germany; 8 Department of Medicine, City Hospital Braunschweig, Braunschweig, Germany; 9 Department of Hematology/Oncology, Georg-August- University, Goettingen, Germany; 10 Department of Internal Medicine III, Johannes-Gutenberg-University, Mainz, Germany; 11 Robert-Ro ¨ ssle-Clinic at the HELIOS Clinic Berlin-Buch, Charite ´, Campus Buch, Berlin, Germany; 12 Practice for Hematology/ Oncology, Saarbruecken, Germany; 13 Practice of Hematology/Oncology, Koeln, Germany; 14 Department of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 15 Department of Internal Medicine I, University of Cologne, Cologne, Germany; 16 Department of Hematology and Oncology, Kliniken Maria Hilf, Mo ¨ nchengladbach, Germany and 17 Department of Haematopathology and Lymph Node Registry Kiel, Schleswig-Holstein University Hospitals, Campus Kiel, Kiel, Germany Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem’s macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n ¼ 34) or CHOP (n ¼ 30). R-CHOP resulted in significantly higher overall res- ponse (OR) rate (94 vs 67%, P ¼ 0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P ¼ 0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P ¼ 0.0033) and in the WM subgroup (P ¼ 0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM. Leukemia (2009) 23, 153–161; doi:10.1038/leu.2008.261; published online 25 September 2008 Keywords: lymphoplasmacytic lymphoma; waldenstroem’s macroglobulinemia; rituximab; immunochemotherapy Introduction In the current World Health Organization (WHO) classification, lymphoplasmacytic lymphoma (LPL), the former immuno- cytoma of the lymphoplasmacytic type in the Kiel classification, 1 is described as a rare indolent CD20-positive B-cell lymphoma, which is characterized by elements ranging from small lymphocytes, lymphoplasmacytoid forms to mature plasma cells. A subgroup of LPL patients represents with monoclonal immunoglobulin M (IgM) paraproteinemia and bone marrow involvement. These cases irrespective of the IgM serum concentration are defined as Waldenstroem’s macroglobuline- mia (WM). WM is considered to be a distinct clinicopatholo- gical entity and often presents with typical clinical symptoms, such as peripheral neuropathy or hyperviscosity syndrome, associated with IgM monoclonal gammopathy. 2–4 There are only few clinical studies reported in LPL: in a retrospective analysis treatment outcome was analyzed in 126 patients with immunocytoma according to the Kiel classification, including 24 patients with lymphoplasmacytic histology. In all, 13 of the 24 patients with lymphoplasmacytic histology were classified as WM. Patients were treated with various chemotherapy regimens including cyclophosphamide, vincristine and prednisone (CVP)-, doxorubicin- or fludarabine-containing regimens be- tween 1972–1996, but only incomplete responses of short duration were documented. 5 In contrast to LPL, multiple phase II studies tested the efficacy of chemotherapy in WM: the standard front-line therapy in WM has been the use of alkylating agents or purine analogs, such as chlorambucil or fludarabine, respec- tively. However, the clinical activity of these compounds is limited: in a meta-analysis of 217 patients with WM treated with mostly chlorambucil, the overall response (OR) rate was 48% with a complete remission (CR) rate of 2%. 6 In a large nonrandomized study, fludarabine single-agent therapy induced a response in 36% of 182 patients with WM and a CR in 2% of cases. 7 In a randomized trial, fludarabine was significantly superior to a combination therapy of cyclophosphamide, doxorubicin and prednisone with a response duration of 19 vs 3 months in 92 patients with relapsed or primary refractory disease. 8 In a phase II study, analyzing 49 patients, the combination of fludarabine and cyclophosphamide achieved Received 24 June 2008; revised 30 July 2008; accepted 12 August 2008; published online 25 September 2008 Correspondence: Professor C Buske, Department of Medicine III, University of Munich, Campus Grohadern, Marchioninistr. 15, Mu ¨nchen 81377, Germany. E-mail: christian.buske@med.uni-muenchen.de Leukemia (2009) 23, 153–161 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu